Variants in and Other Mendelian Deafness Genes Are Associated with Cisplatin-Associated Ototoxicity.

Cisplatin is one of the most commonly used chemotherapy drugs worldwide and one of the most ototoxic. We sought to identify genetic variants that modulate cisplatin-associated ototoxicity (CAO). We performed a genome-wide association study (GWAS) of CAO using quantitative audiometry (4-12 kHz) in 511 testicular cancer survivors of European genetic ancestry. We performed polygenic modeling and functional analyses using a variety of publicly available databases. We used an electronic health record cohort to replicate our top mechanistic finding. One SNP, rs62283056, in the first intron of Mendelian deafness gene (wolframin ER transmembrane glycoprotein) and an expression quantitative trait locus (eQTL) for met genome-wide significance for association with CAO ( = 1.4 × 10). A significant interaction between cumulative cisplatin dose and rs62283056 genotype was evident, indicating that higher cisplatin doses exacerbate hearing loss in patients with the minor allele ( = 0.035). The association between decreased expression and hearing loss was replicated in an independent BioVU cohort ( = 18,620 patients, Bonferroni adjusted < 0.05). Beyond this top signal, we show CAO is a polygenic trait and that SNPs in and near 84 known Mendelian deafness genes are significantly enriched for low values in the GWAS ( = 0.048). We show for the first time the role of in CAO and document a statistically significant interaction between increasing cumulative cisplatin dose and rs62283056 genotype. Our clinical translational results demonstrate that pretherapy patient genotyping to minimize ototoxicity could be useful when deciding between cisplatin-based chemotherapy regimens of comparable efficacy with different cumulative doses. .